Dihydroquinidine polygalacturonate and dihydroquinidine galacturonate compositions



United States Patent 3,525,790 DIHYDROQUINIDINE POLYGALACTURONATE ANDDIHYDROQUINIDINE GALACTURON- ATE COMPOSITIONS Alfred Halpern, GreatNeck, N.Y., assignor, by mesne assignments, to Synergistics, acopartnership consisting of Mortimer D. Sackler and Raymond R. Sackler,Yonkers, N .Y.

No Drawing. Application Mar. 21, 1966, Ser. No. 535,736, which is acontinuation-in-part of application Ser. No. 373,827, June 9, 1964.Divided and this application Aug. 21, 1968, Ser. No. 772,880

Int. Cl. A61k 27/00 US. Cl. 42 l-ll80 12 Claims ABSTRACT OF THEDISCLOSURE Pharmaceutical compositions containing dihydroquinidinepolygaiacturonate and dihydroquinidine galacturohate are describedtogether with the method for treating cardiac arrhythmias therewith.

This application is a division of application Ser. N0. 535,736, filedMar. 21, 1966, now abandoned, which was a continuation-in-part ofapplication Ser. No. 373,827, filed June 9, 1964, and now abandoned.Application Ser. No. 761,819, filed Sept. 23, 1968, now Pat. No.3,479,359, is a continuation-in-part of application Ser. No. 535,736.

This invention relates to new therapeutically important derivatives ofthe alkaloid dihydroquinidine which are formed by the interaction of aglycose component and the alkaloidal radical. In particular, thisinvention is concerned with dihydroquinidine polygalacturonate anddihydroquinidine galacturonate, the methods for their preparation,pharmaceutical compositions containing these compounds and the method ofreversing a cardiac arrhythmia by administration of the newdihydroquinidine glycose compounds and compositions containing saidcompounds.

Disorders in the rhythm of the heart are among the very common problemsencountered in medical practice. It has been estimated that about 25percent of the average cardiac population presents the problems ofdisordered heart rhythm. The number of these cases does not, however,satisfactorily reflect the importance of a drug Which is effective incontrolling this disturbance since, among another sizeable group, theabnormal rhythms take on the aspect of other serious heart disease andamong these, depending on the kind of disorder of the heart rhythm, thetype of patient, and the condition of the heart are included thefollowing symptoms: cardiac neurosis, panic, palpitation, cough, attacksof syncope, cardiac pain, pulmonary edema, congestive failure, emboli,shock and death. In many instances, however, the patient with theabnormal rhythm has a condition which is of no great consequence to him,efiecting neither his ability to carry on nor his longevity. In manypatients, the arrythmias produce no overt symptoms and the disorder ofthe rhythm may first be discovered as an incident during an examinationfor some other purpose.

While cinchona bark contains more than twenty alkaloids, quinidine isthe most important member of this group indicated for the treatment ofdisorders of the heart and the largest part of the clinical literatureon the cardiac action of the cinchona alkaloids relates entirely toquinidine. Disorders of the cardiac rhythm constitute the onlytherapeutic indication for the use of quinidine in disturbances of theheart. It has no primary place in the treatment of cardiac pain orfailure. While under some conditions quidine acts to prevent or abolishcardiac pain or failure, such results are due neither to the directdilataice tion of the coronary arteries nor to the direct action of theforce of contraction of the cardiac muscles, and quinidine remains thedrug of choice in the treatment of the abnormal rhythms of the heart.

Some of the inherent limitations to the use of quinidine inclinicalcardiology and the experimental approaches to correct these aredescribed in US. Pat. 2,878,252. Clinical literature recognizes stillanother probem associated with the use of quinidine to correct theabnormal heart rhythm and that is, that it is effective only inapproximately percent of the cardiac arrhythmias. While a portion ofthese patients who are not benefited by the administration of the olderquinidine compound may be benefited by the administration of the newerquinidine compound derivatives, there remains a significant group forwhom quinidine exerts no therapeutic affect on their cardiacarrhythmias. This group of patients are often treated With other potentagents such as digitalis, adrenergic drugs and procaine amide, butusually without significant effect and the arrhythmia continues topersist for the remainder of their lives, causing varying degrees oflimitation and distress.

Among the alkaloids isolated from the cinchona plant is the hydrogenatedform of quinidine. This compound is known as dihydroquinidine and may bedistinguished from quinidine in its chemical, physical, pharmacologicand therapeutic properties. Irrespective of the structural relationshipbetween quinidine and dihydroquinidine, there is a marked contrast inbehavior of the hydrogenated and the compounds. Apart from the wellknown generic dillerences between the hydrogenated and unhydrogenatedcompounds, these separate entities have their own level of chemicalreactivity and toxicologic reactivity, and the chemical behavior of onemember of the cinchona alkaloid group may not be imputed to anothermember of the same group. Thus, it is known that the presence of anunsaturated or unhydrogenated linkage in an organic compound willinterfere with physiologic enzyme reactions and also that the hydrogenunsaturation of an organic compound may convert an essentially benignsubstance into a noxious irritant, as for example, compare theproperties of alkyl alcohol and its saturated analog, propyl alcohol.The United States Pat. No. 2,230,631, notes in column 1 (lines 36through 52), that dihydro quinidine nicotinate is a crystalline solidmelting at 209 C. and is slightly soluble in water. The very nextparagraph (colume 1, lines 52-68) of the same reference, describes thepreparation and properties of quinidine nicotinate as a non-crystallinesubstance, without a melting point and which is easily soluble in water.Here we find that a physical and chemical change in the state of matterand its properties results from the simple chemical reaction of a saltformation when nicotinic acid is reacted with the separate reagents,quinidine and hydroquinidine. Whereas the hydrogenated dihydroquinidineproduces a crystalline, slightly water-soluble reaction-product; thedehydrogenated quinidine results in a non-crystalline glassy material,which is easily soluble in water.

Pharmacologically quinidine may be distinguished from dihydroquinidinethan of dihydroquinidine were required to prevent electrically inducedauricular fibrillation, while the dose of dihydroquinidine required toabolish the after-affects to faradic stimulation was higher than that ofquinidine. The toxicity of dihydroquinidine in mice is about 18 percentgreater than the pure quinidine. Dihydroquinidine, (Chem. Abstracts, 489543b, 1954), is reported to reduce muscle potassium and accelerateliver and myocardial potassium loss during therapeutic use. This effectis in contradistinction to the properties of quinidine, which has beenreported to augment muscle potassium (Proc. Soc. Exper. Med. & Biol, 92:629,

1956) (Am. J. Physiol. 199; 151, 1960). While some investigators haveshown that dihydroquinidine and pure quinidine were similar in thequalitative nature of their therapeutic action, on a weight for weightbasis, dihydroquinidine appears to be clinically more potent. While theearly references to a therapeutic equivalence of dihydroquinidine andquinidine appeared approximately 40 years ago, in the interim, moredefinitive experimental techniques have been developed and as a resultof the broadening of the knowledge in this specialized fieldtherapeutics, many limitations to the older experimental procedures havebeen established. Thus, some investigators, as for example Van Dongen,(Arch. Internat. De Pharmacodyn et de Therap., 63: 90-94, 1939) whooriginally proposed that dihydroquinidine is a more potent substancethan quinidine, later abandoned this concept after continued research,(Arch. Internat. Pharmacodyna. et de Therap., 91: 399-403, 1952), DeBoer also assumed, in 1936 (Proc. Acad. Sci., Amsterdam, 39': 266- 271,1936) that dihydroquinidine was a better anti-fibrillatory agent than isquinidine but on the basis of subsequent studies (Arch. Internat. dePharmacodyn et de Therap., 51: 246-254, 1939) he reversed his positionand concluded that quinidine is perhaps the more suitable therapeuticagent. A study of the literature establishes that many of the earlierworkers later reversed their earlier position regarding the relativepotencies of quinidine and dihydroquinidine and in view of the manyinconsistent findings in the scientific literature, the therapeuticproperties determined for one compound may not be imputed to the othercompound.

It was found that dihydroquinidine polygalacturonate anddihydroquinidine galacturonate are especially useful to correctarrhythmias in those patients who are refractory to the conventionalforms of quinidine and who would otherwise remain cardiac invalids, withserious threat to their life.

A comparative clinical study of quinidine polygalacturonate, quinidinehydrochloride and dihydroquinidine polygalacturonate was conducted in aseries of 21 patients presenting cardiac arrhythmias. Each of thepatients received a complete physical examination which includedelectrocardiographic analysis of the patients cardiac status prior tothe start of the study. The method of study utilized was as follows: Thepatients were prescribed one of the test compounds, to wit: quinidinepolyquinidine hydrochloride and the cardiodynamic effects observed. Across-over procedure was then utilized, with the patients receivinganother test compound for clinical comparison of the cardiodynamiceffects. In this manner, the specific antiarrhytmic properties of therespective test compounds were compared Within the same patient. Thus, 7patients were first treated with quinidine hydrochloride and then withdihydroquinidine polygalacturonate and 11 patients were treated firstwith quinidine polygalacturonate and then with dihydroquindinepolygalacturonate. The results of this study are presented in Table I,following. The conclusions of the investigator, based upon the resultsof his study of the effects of quinidine hydrochloride, quinidinepolygalacturonate and dihydroquinidine polygalacturonate in the seriesof patients described in Table I, are as follows:

(a) The total therapeutically successful dosage administration fordihydroquinidine polygalacturonate is lower than that amount requiredfor quinidine hydrochloride and quinidine polygalacturonate. The controlof the arrhythmia could generally be achieved on lower daily dosage ofdihydroquinidine polygalaceuronate than with either quinidinehydrochloride or quinidine polygalacturonate. Dihydroquinidinepolygalacturonate exerts more protracted and pronounced cardiodynamiceifects than quinidine polygalacturonate.

(b) Dihydroquinidine polygalacturonate did not cause any side reactionssuch as nausea or diarrhea, which were observed after administration ofquinidine polygalacturonate and quinidine hydrochloride. This absence ofgastrointestinal irritation is important, since dihydroquinidinepolygalacturonate was administered after the onset of side reactionswith quinidine polygalacturonate or quinidine hydrochloride, in the samepatient.

(c) The superior properties of dihydroquinidine polygalacturonate ascompared with quinidine hydrochloride and quinidine polygalacturonate,could not have been anticipated from a knowledge of the literature andthe known behavior of these compounds.

These unusual properties of the new glycose acid derivatives ofdihydroquinidine are in contrast to the reported research findings withhydroquinidine per se, in that its pharmacologic effect is identical tothat of quinidine alkaloid and also that dihydroquinidine possesses noclinical advantages over the conventional quinidine preparations.Furthermore, this unusual and desirable property of dihydroquinidinepolygalacturonate and dihydroquinidine galacturonate is not due to anyvariations in the potency of the dihydroquinidine moiety, since thislatter compound has been described as being only slightly more potentthan quinidine by some investigators and of equal or lesser potency byothers. Neither can the clinical differences between dihydroquinidineand quinidine be ascribed to a preferential solubility and absorption ofthe former drug, since the solubility and absorption of both thesecompounds have been found to be virtually the same.

Dihydroquinidine polygalacturonate exhibits new and unexpectedproperties were compared with quinidine polygalacturonate in that itexerts an effect which is more protracted as well as more pronouncedthan that of quinidine polygalacturonate. This finding is of particularclinical significance since it affords a means for correcting cardiacarrhythmias which are not amenable to treatment with either quinidineinorganic acid salts or quinidine polygalacturonate. The advantage tothe physician of having available a drug which exhibits a more intensiveeffect in controlling heart rhythm cannot be minimized. Thus, thesuperiority of dihydroquinidine polygalacturonate over quinidinepolygalacturonate opens a new avenue of therapy for the cardiologist inthe management of the patient with cardiac arrhythmias. These unusualand desirable antiarrhythmic property of these new agents which occursin those patients who have been found to be refractory to theconventional salts of quinidine, is a finding which cannot be predictedon the known behavior of dihydroquinidine.

Dihydroquinidine polygalacturonate and dihydroquinidine galacturonatemay be prepared through the interaction between polygalacturonic acid orgalacturonic acid and dihydroquinidine in an inert medium. Therespective compounds also may be formed through the interaction of thealkali salts of the polygalacturonic acid or galacturonic acid with theacid salt of the dihydroquinidine, as for example, dihydroquinidinesulfate, or dihydroquinidine hydrochloride. When dihydroquinidinepolygalacturonic acid is being prepared, it is first necessary todetermine the neutralization equivalent of the acid in order that itscombining power with the dihydroquinidine base be known. Thisneutralization equivalent will vary with the polymer chain length whichmay range in molecular weight of from 20,000 to 80,000. The polymer iscomposed of units of galacturonic acid and consequently the saltdihydroquinidine polygalacturonate consists of multiples ofdihydroquinidine galacturonate which may range from 50 to 400 units ormore. In the course of conducting this reaction, the separate componentsare dispersed, or dissolved, in equal portions of the inert solvent.Examples of the said inert solvents which may be used are water,alkanols of from 1 to 6 carbons, acetone and mixtures of these. Apreferred inert medium is isopropyl alcohol. The alkaline component isadded slowly to the acid component while the mixture is being stirredand gently heated (no greater than 50 C.). When all of the base moietyhas been added, the stirring is continued until the pH of the reactionmixture is between pH 4 and pH 7. The solvent is then evaporated and theresidue extracted with chloroform, dried and washed with water.

Dihydroquinidine polygalacturonate is obtained as a tannish to creamyWhite solid, with a characteristic melting point, which analyzes in goodagreement with its theoretical values for carbon, hydrogen and nitrogen.The molecule is somewhat hygroscopic, containing two molecules of waterof hydration. The ultraviolet spectrum obtained for this compoundestablishes the presence of the dihydroquinidine moiety and on treatmentwith aqueous alkali it is decomposed to yield a precipitate of theinsoluble dihydroquinidine base while an aqueous acid solutionprecipitates the polygalacturonic acid moiety from a dispersion of thecompound. Dihydroquinidine polygalacturonate is slightly soluble inwater but insoluble in methanol, ethanol, chloroform and ether. Thebitter taste of dihydroquinidine is modified by reacting it withpolygalacturonic acid. The compound is stable for further pharmaceuticalmanufacturing.

Dihydroquinidine galacturonate is obtained through the interreaction ofstoichiometric proportions of dihydroquinidine base and galacturonicacid in an inert medium, such as water, alkanols of from 1 to 6 carbons,or mixtures of these. The reaction is carried out in a suitable glassvessel to which is first added a solution of the galacturonic acid andwith the aid of gentle heat and with stirring, small increments ofdihydroquinidine base are added to this. When all of thedihydroquinidine base has been added, the solution is warmed to refluxtemperature, allowed to cool to room temperature and set aside tocrystalize in an ice-chest.

Dihydroquinidine galacturonate is a tan to white crystaline solid whichmelts at 134-136 C. It is soluble in water and alcohol and insoluble inether and chloroform. Although the aqueous solution darkens on exposureto air and light, it is stable for pharmaceutical compounding purposes.It has the characteristic ultraviolet spectrum of dihydroquinidine andon treatment with alkali is decomposed so that the dihydroquinidine baseprecipitates.

When it is desired to utilize these new compounds in therapy, they maybe administered in the form of tablets, capsules, powders granules orsuppositories. Liquid dosage forms such as syrups, solutions, elixirsand tinctures may also be utilized. Irrespective of the dosage formselected, the concentration of active compound per unit dose ranges from200 mg. to 200 mg. The new compounds may be administered from 1 to timesdaily in order to achieve a conversion of the arrhythmia a normal sinusrhythm. Maintenance therapy will usually require from 200 to 400 mg. ofthe active compound administered once or twice daily.

In certain circumstances it may be desired to utilize parenteral therapyto achieve the antiarrhythmic effect.

A solution of dihydroquinidine galacturonate may be utilized forparenteral therapy and a dosage of from 200 mg. to 400 mg. isadministered by intramuscular or intravenous injection. Although cautionmust be exercised when intravenous injection is utilized, the compoundpossesses suflicient freedom from local toxicity to be usedsatisfactorily by the intramuscular route. In practice it will be founddesirable to dissolve the therapeutic dose requirement in a volume offrom 2 to 4 cc., so that each 2 cc. of solution will contain 200 mg. ofdihydroquinidine galacturonate. It should be noted that the same totaldose requirements are necessary to reverse the cardiac arrhythmias whenthese drugs are administered by either the oral or the parenteralroutes, so that the initial dosage required to reverse the arrhythmias,remains from 200 to 800 mg. of dihydroquinidine glacturonate, with themaintenance dosage of 200 to 400 mg. per day of the parenteral solution.Dihydroquinidine polygalacturonate exhibits an unexpected increasedsolubility in aqueous fluids. While it should be expected that theformation of a polymeric compound would render the resultant productinsoluble in aqueous fluids, a contrary condition was found to be inexcess of 5 percent and specifically, about 8.5 percent.

When it is desired to utilize the subject compounds in therapy tocorrect cardiac arrhythmias then the respective dosage forms describedabove are administered for a series of 5 doses, at 2 to 3 hour intervalsfor 1 day. This course of therapy will convert the arrhythmia to anormal sinus rhythm in the majority of cases. However, in those patientswherein the arrhythmia still persists, a second and even a third courseof therapy may be utilized. After the achievement of a normal sinusrhythm, maintenance dosage of from 200 mg. to 400 mg. administered onceor twice daily, will generally be found satisfactory to maintain thenormal sinus rhythm. Parenterally, the administration ofdihydroquinidine galacturonate will cause a satisfactory maintenanceeffect when administered in a dosage range of 200 mg. to 400 mg. perday. When the pharmaceutical dosage forms of dihydroquinidinepolygalacturonate are compared with those of quinidinepolygalacturonate, unexpected advantages are observed. Dihydroquinidinepolygalacturonate will be found to cause a more pronounced action whichpersists for a longer period than that of quinidine polygalacturonate aswell as quinidine inorganic acid salts. There are no noxious sidereactions such as nausea and diarrhea after the administration of thenew compounds and they are excreted from the body at a rate which doesnot lead to accumulation. This favorable rate of excretion permits theadministration of multiple dosages without additive effects andcumulative toxicity. The rapid onset of action and the uniform bloodlevels resulting after the administration of dihydroquinidinepolygalacturonate permits a more desirable control of the cardiacarrhythmia than has hiterto been possible with derivatives of thecinchona plant. The active compounds are readily assimilated andabsorption and the beneficial cardiotonic eifects will be observed totake eifect within 15 minutes after administration.

The following examples illustrate the scope of this invention.

EXAMPLE 1 The neutralization equivalent of a sample of polygalacturonicacid is determined by titration with one-tenth normal alkali.

In a round-bottom, three-neck flask fitted with a stirrer, a droppingfunnel and a condenser, is placed 1 liter of 50 percent (VOL/vol.)mixture of isopropyl alcohol and water. To this is added, with stirring,gm. of polygalacturonic acid and when complete dispersion has beenobtained, the stoichiometric equivalent of dihydroquinidine alkaloiddissolved in just sufficient isopropyl alcohol, is slowly added. The pHof the reaction mixture is determined periodically and the mixture isgently warmed (below 50 C.). After about 4 hours or when the pH hasstabilized between the range of from pH 4 to pH 7, the stirring isstopped and the mixture cooled to 0 C., and filtered. The solvent isthen evaporated under reduced pressure (10 mm./Hg) and the residueextracted with two volumes of hot chloroform and dried. The dried powderis then suspended in two volumes of 50 percent water methanol andfiltered. The insoluble powder is dried and is dihydroquinidinepolygalacturonate. The compound is tannish to white in colorand melts(with decomposition) at 205207 C. and possesses two molecules of waterof hydration. The empirical formula for the compound is C H N O -H O,with a calculated molecular weight of 556.54. The compound is insolublein chloroform, ether and methanol, and slightly soluble in water. Itpossesses a characteristic ultraviolet spectrum for dihydroquinidine anda characteristic infrared spectrum which is different from that of itscomponents or a mixture of these. It analyzes in good agreement with itstheoretical values of carbon, nitrogen and hydrogen.

9 Theory: Carbon: 56.1%; hydrogen: 7.2% nitrogen:

5.0% Found: Carbon: 55.87%; hydrogen: 7.09%; nitrogen:

EXAMPLE 2 EXAMPLE 3 A solution containing 200 grams of polygalacturonicacid in two liters of 60 percent mixture of methanolwater is prepared,with the aid of an exact neutralization equivalent of sodium hydroxide.The solution is stirred and to this is added a solution consisting of anexact equivalent of dihydroquinidine sulfate (based upon theneutralization equivalent determined for the polygalacturonic acid). Thedihydroquinidine sulfate is dissolved in a just sufiicient quantity of60 percent mixture (vol./ vol.) methanol-water. The mixture is warmed to60 C. and after the pH of the solution has stabilized within the rangeof pH 4 to pH 6, an additional liter of methanol is added. The mixtureis then cooled to C. and filtered. The solvent is evaporated to dryness,the residue is washed with two 50 cc. portions of water and dried. Theresulting product is dihydroquinidine polygalacturonate which melts at205-207" C. and corresponds in every way to that obtained as a result ofExample 1.

EXAMPLE 4 In place of dihydroquinidine sulfate used in Example 3 above,may be substituted in equimolar proportions dihydroquinidine chloride,dihydroquinidine bromide and dihydroquinitline nitrate.

In place of the sodium hydroxide used to neutralize the polygalacturonicacid in Example 3 above, may be substituted, in equirnolar proportions,a metal hydroxide, carbonate and bicarbonate in which the molecularweight of the metal ion is less than 55, as for example, lithium,potassium, calcium, magnesium and aluminum.

EXAMPLE 5 To a solution of one-tenth mol of galacturonic acid dissolvedin 500 cc. of butyl alcohol is added exactly onetenth mol ofdihydroquinidine. The mixture is stirred and warmed to refluxtemperature for 2 hours and the solvent evaporated to dryness underreduced pressure. The residue is extracted with chloroform and dried.The resulting product is dihydroquinidine galacturonate which melts at134 to 136 C. and is a tan to white crystalline substance, soluble inwater and methanol, ethanol, acetone and insoluble in chloroform andether. The ultraviolet spectrum is characteristic for dihydroquinidineand the com pound is decomposed by alkali to result in an insolubleprecipitate of dihydroquinidine base.

EXAMPLE 6 In place of the butyl alcohol used in Example 5 above, may besubstituted a member of the group of alkanols containing from 1 through4 carbon atoms, water and mixtures of these. The remainder of the stepsare the same and the resultant product is identical to that obtained asa result of Example 5.

EXAMPLE 7 To a solution of 1 mol of sodium galacturonate dissolved in 1liter of ethanol is added one mol of dihydroquinidine chloride dissolvedin 1 liter of ethanol, and 500 mg. of copper powder. The mixture isstirred and heated to about 60 C. A copious precipitate forms as thereac- 10 tion progresses, and after 4 hours the stirring is stopped; themixture filtered and the solvent evaporated to dryness. The residue isextracted with 25 cc. of chloroform, dried and dissolved in a justsuflicient quantity of hot isopropyl alcohol. The solution is filtered,set aside to crystallize in an ice-chest. The crystals are collected ona filter, dried and melt at l34-l36 C. and correspond todihydroquinidine galacturonate.

EXAMPLE 8 In place of the sodium galacturonate used in Example 7 above,may be substituted in equimolar amounts a metal hydroxide, carbonate andbicarbonate in which the molecular weight of the metal ion is less than55, as for example, lithium, potassium, calcium, magnesium and aluminum.

In place of the dihydroquinidine chloride used in Example 7 above, theremay be substituted in equimolar quantities, dihydroquinidine sulfate,dihydroquinidine nitrate and dihydroquinidine bromide.

EXAMPLE 9 When it is desired to administer the new compounds in therapy,then they may be utilized in the form of tablets, capsules, powders,granules or suppositories. The quantity of active ingredient in therespective pharmaceutical dosage form ranges 200 mg. to 800 mg. per unitdose. For the preparation of the tablets, capsules, powders andgranules, a basic granulation mixture is prepared by mixing the activecompound with from 1 to 10 parts of a pharmaceutically acceptablediluent selected from the group consisting of lactose, sucrose,dextrose, starch, sorbitol, mannitol or mixtures of these. Afterthorough mixing, the whole is 'wetted with a 50 percent ethanolwatermixture and air-dried. In the preparation of tablets, suitable binders,such as gum acacia and gum tragacanth, are added at a concentration of0.1 percent to 1 percent by weight, and a tablet lubricant, as forexample, magnesium stearate, is added at a concentration of up to 0.5percent by weight and the whole granulated with ethanolwater granulatingsolution, as described above. The granulation is then compressed intotablets of suitable size and shape, so as to contain from 200 mg. to 800mg. of active ingredient per tablet.

In the preparation of capsules, the basic granulation or the activeingredient alone may be filled into a capsule of suitable size andshape. The dosage of active compound per capsule is from 200 mg. to 800mg. of active compound.

In the preparation of powders and granules, the basic granulationdescribed above is utilized. For the prepara tion of powders, theparticle size of the granulation is reduced to a No. 60 standard meshsize or finer. For the preparation of granules the particle size is thatobtained by passing the granulation mixture through a No. 8 standardmesh screen. Suitable flavoring and coloring matter may be added to thegranules and powders, if desired. For both powders and granules the unitdose is 1 teaspoonful (5 grams) each unit dose containing from 200 mg.to 800 mg. of active compound.

For the preparation of suppositories the active compound may be mixedwith a pharmaceutically suitable suppository base, as for example, cocoabutter, polyoxyethylene glycol, having an average molecular weight offrom 1500 to 6000 and which are known in the trade as Carbowaxes,spermacetti, glycerol-gelatin suppository base, or any otherpharmaceutically suitable suppository vehicle. The active ingredient isdispersed in the suppository base by means of levigation. Either thecold extrusion process or the hot pour technique may be utilized for themanufacture of suppositories. Each suppository will contain from 200 mg.to 800 mg. of the active compound.

Should it be desired to utilize liquid dosage forms, then these may beprepared utilizing a pharmaceutically acceptable vehicle such asethanol, glycerin, propylene glycol, sorbitol, water and mixtures ofthese. Suitable flavoring and sweetening agents may be added and syrupmay also be used as a vehicle for the preparation of liquid dosageforms. The active ingredient is dispersed in the preferred liquidpharmaceutically acceptable vehicle, so that each cc. (1 teaspoon) willcontain from 200 mg. to 800 mg. of the active compound.

EXAMPLE In place of the dihydroquinidine polygalacturonate used inExample 9, may be substituted in equivalent amounts, dihydroquinidinegalacturonate to prepare tablets, capsules, powders, granules andsuppositories, as well as the liquid dosage forms.

When an aqueous injectable solution of dihydroquinidine galacturonate isdesired, the solution is prepared so that the concentration ofdihydroquinidine galacturonate is from 200 to 400 mg. per cc. ofsolution. Using an aseptic technique, the correct amount ofdihydroquinidine galacturonate is dissolved in the total volume requiredof water-for-injection. Gentle heat may be utilized to achieve solution,but this is not necessary. When all of the dihydroquinidine hasdissolved, the solution is filtered through a selas bacteriologic filterand additional waterfor-injection added, so that the final volumecontains from 200 to 400 mg. of dihydroquinidine galacturonate per 2 cc.of solution. The solution is then packaged in amber glass ampules andmay be sterilized by autoclaving.

EXAMPLE 1 1 When it is desired to correct the cardiac arrhythmias, asfor example, atrial fibrillation, atrial flutter, paroxysmal atrialfibrillation, paroxysmal atrial tachycardia, premature atrialcontractions and premature ventricular contractions, eitherdihydroquinidine polygalacturonate or dihydroquinidine galacturonate maybe administered in the form of capsules, tablets, powders, granules,suppositories and liquid dosage forms. Dihydroquinidine galacturonatemay be injected intramuscularly or intravenously. Irrespective of theroute of administration or the particular dosage form employed, theamounts of the therapeutic compound used will be the same for therespective dosage form selected. Thus, it will be found that 200 mg. to400 mg. of either dihydroquinidine polygalacturonate or dihydroquinidinegalacturonate administered every 2 to 3 hours for 5 doses, will revertthe arrhythmia to a normal sinus rhythm in a preponderance of patients.A maintenance dosage of 200 to 400 mg., once or twice a day, of therespective active compound may then be instituted to sustain thetherapeutic effects observed.

When there is no urgency in obtaining a reversion of the arrhythmia, thepatient may be prescribed a dosage of from 200 to 400 mg. of theselected compound, three to four times daily, for a period of 3 to 4days. If the desired response is not obtained with this dosage level,the total daily requirement is increased by 200 mg. of the selectedcompound, per day, for an additional two-day period, with subsequentincreases of 200 mg. of the compound per day after similar intervals,until a normal sinus rhythm is achieved.

A maintenance regimen of from 200 to 400 mg. once or twice a day, of theselected compound, as for example, dihydroquinidine polygalacturonate,dihydroquinidine 12 galacturonate, is then instituted to sustain thetherapeutic results achieved. The utilization of this slower procedurefor reversing the cardiac arrhythmia will be found to be successful in apreponderant number of patients who are refractory to other forms ofantiarrhythmic therapy.

I claim:

1. A pharmaceutical composition in unit dosage form for treating cardiacarrhythmia comprising from 200 mg. to 800 mg. of a compound selectedfrom the group consisting of dihydroquinidine polygalacturonate anddihydroquinidine galacturonate and a pharmaceutical carrier therefor.

2. A pharmaceutical composition as described in claim 1, said compoundbeing dihydroquinidine polygalacturonate.

3. A pharmaceutical composition as described in claim 1, said compoundbeing dihydroquinidine galacturonate.

4. The method of treating cardiac arrhythmia in a patient sufferingtherefrom which comprises administering to said patient anantiarrhythmic amount of a pharmaceutical composition as described inclaim 1.

5. The method of claim 4, said pharmaceutical composition comprisingfrom 200 mg. to 800 mg. of dihydroquinidine polygalacturonate and apharmaceutical carrier therefor.

6. The method of claim 4, said pharmaceutical composition comprisingfrom 200 to 800 mg. of dihydroquinidine galacturonate and apharmaceutical carrier therefor.

7. The method of treating a cardiac arrhythmia in a patient sufferingtherefrom which comprises administering to said patient from 1 to 5times daily a unit dosage form of a pharmaceutical composition asdescribed in claim 1.

8. The method of claim 7, said pharmaceutical composition comprisingfrom 200 to 800 mg. of dihydroquinidine polygalacturonate and apharmaceutical carrier therefor.

9. The method of claim 7, said pharmaceutical composition comprisingfrom 200 to 800 mg. of dihydroquinidine galacturonate and apharmaceutical carrier therefor.

10. The method of treating cardiac arrhythmia in a patient suiferingthererom which comprises administering to a said patient anantiarrhythmic amount of a compound selected from the group consistingof dihydroquinidine polygalacturonate and dihydroquinidinegalacturonate.

11. The method of claim 10, said compound being dihydroquinidinepolygalacturonate.

12. The method of claim 10, said compound being dihydroquinidinegalacturonate.

References Cited UNITED STATES PATENTS 2,049,442 8/ 1936 Haegland260-284 2,111,227 3/1938 Salzberg 260284 2,230,631 2/1941 Thomas 260-2842,878,252 3/1959 Halpern 260284 ALBERT T. MEYERS, Primary Examiner H. M.ELLIS, Assistant Examiner US. Cl. X.R. 424259

